The present invention relates to novel biaromatic compounds and to pharmaceutical/cosmetic compositions comprised thereof; the subject compounds are especially useful in human or veterinary medicine, or, alternatively, in cosmetic compositions.
The compounds according to the invention have pronounced activity in the fields of cell differentiation and proliferation, and are particularly useful in the topical and systemic treatment of dermatological conditions associated with a keratinization disorder, dermatological (or other) conditions including an inflammatory and/or immunoallergic component, and dermal or epidermal proliferations, whether benign or malignant. The subject compounds can also be used for the treatment of degenerative diseases of connective tissue, to combat aging of the skin, whether photoinduced or chronological aging, and to treat cicatrization disorders. They are also useful for ophthalmological applications, especially for the treatment of corneopathies.
The compounds according to the invention can also be formulated into cosmetic compositions for body and hair hygiene.
Briefly, the bicyclic aromatic compounds according to this invention have the following structural formula (I): 
in which R1 is (i) the radical xe2x80x94CH3, (ii) a radical xe2x80x94CH2OR2, or (iii) a radical xe2x80x94COxe2x80x94R3, wherein R2 and R3 are as defined below; Ar1 is a radical selected from among those of the following formulae (a)-(c): 
wherein R4, R5, R6, R7, R8, R9, R10 and R11 are as defined below; Ar2 is a radical selected from among those of the following formulae (d)-(h): 
wherein R12 and R13 are as defined below; X is a radical selected from among those of the following formulae (i)-(l): 
wherein R14, R15 and Y are as defined below; R2 is a hydrogen atom, a lower alkyl radical or a radical xe2x80x94COxe2x80x94R16, wherein R16 is as defined below; R3 is a hydrogen atom, a lower alkyl radical, a radical of the formula: 
wherein Rxe2x80x2 and Rxe2x80x3 are as defined below, or a radical xe2x80x94OR17, wherein R17 is as defined below; R4 is a hydrogen atom, a polyether radical, a lower alkyl radical, or a radical xe2x80x94OR18, wherein R18 is as defined below; R5 is a hydrogen atom, a lower alkyl radical, a polyether radical, or a radical xe2x80x94OR19, wherein R19 is as defined below; R6 is a tert-butyl radical; R7 is a lower alkyl radical, a polyether radical, or a radical xe2x80x94OR20, wherein R20 is as defined below, with the proviso that R6 and R7 may together form, with the carbon atoms from which they depend, a 6-membered ring optionally substituted with at least one methyl group and/or optionally interrupted by an oxygen or sulfur atom; R8 is a tert-butyl, adamantyl, aryl or aralkyl radical; R9 and R10 together form, with the carbon atoms from which they depend, a 5- or 6-membered ring optionally substituted with at least one methyl group and/or optionally interrupted by an oxygen or sulfur atom; R11 is a hydrogen atom, a lower alkyl radical having from 1 to 9 carbon atoms, a hydroxyl radical, an alkoxy radical, a polyether radical or a radical xe2x80x94OR21, wherein R21 is as defined below; R12 is a hydrogen atom, a hydroxyl radical, an alkoxy radical, a polyether radical or a radical xe2x80x94OR22, wherein R22 is as defined below; R13 is a hydrogen atom, a lower alkyl radical, or a radical xe2x80x94COR23, wherein R23 is as defined below; R14 and R15, which may be identical or different, are each a hydrogen atom, or a lower alkyl radical; Y is an oxygen atom or a CH2 radical; R16 is a lower alkyl radical; R17 is a hydrogen atom, a linear or branched alkyl radical having from 1 to 20 carbon atoms, an alkenyl radical, a mono- or polyhydroxyalkyl radical, an optionally substituted aryl or aralkyl radical or a sugar residue; Rxe2x80x2 and Rxe2x80x3, which may be identical or different, are each a hydrogen atom, a lower alkyl radical, a mono- or polyhydroxyalkyl radical, an optionally substituted aryl radical or an amino acid residue, with the proviso that Rxe2x80x2 and Rxe2x80x3 may together form, with the nitrogen atom from which they depend, a nitrogenous heterocycle; R18, R19 and R20, which may be identical or different, are each a hydrogen atom, a lower alkyl radical, an alkenyl radical, a mono- or polyhydroxyalkyl radical, an aryl radical, an optionally substituted aralkyl radical or a radical xe2x80x94(CH2)nxe2x80x94R24, wherein n and R24 are as defined below; R21 and R22, which may be identical or different, are each an alkenyl radical, a mono- or polyhydroxyalkyl radical, an aryl radical, an optionally substituted aralkyl radical, or a radical xe2x80x94(CH2)nxe2x80x94R24, wherein n and R24 are as defined below; R23 is a lower alkyl radical; R24 is a heterocycle, a monohydroxyalkyl radical, a thiol radical optionally substituted with a lower alkyl radical, an amino radical optionally substituted with at least one lower alkyl radical, a radical xe2x80x94COOR25, or a radical xe2x80x94CON(R26)R27, wherein R25, R26 and R27 are as defined below; R25 is a hydrogen atom or a lower alkyl radical; R26 and R27, which may be identical or different, are each a hydrogen atom, a lower alkyl radical, or an optionally substituted aryl radical, with the proviso that R26 and R27 may together form, with the nitrogen atom from which they depend, a nitrogenous heterocycle; n is an integer such that 2xe2x89xa6nxe2x89xa69; with the further provisos that, when Ar1 is the radical of formula (c) and X is a radical of formulae (i) or (j), then R11 is the radical xe2x80x94OR21 or a polyether radical, or when Ar2 is the radical of formula (d), then R12 is the radical xe2x80x94OR22 or a polyether radical, and the compounds of formula (I) do not include those wherein R11 is a methoxymethoxy radical in an ortho position relative to the substituent Ar2 when Ar1 is the radical of formula (c), X is the radical of formula (i), R12 is hydrogen and R1 is the radical xe2x80x94COR3 wherein R3 is the radical xe2x80x94OR17 and R17 is a hydrogen atom, and those wherein R12 is a methoxymethoxy radical in an ortho- or para-position relative to the substituent Ar1 when Ar1 is the radical of formula (c), X is the radical of formula (i), R11 is a methyl radical in an ortho-position relative to Ar2, and R1 is the radical xe2x80x94COR3 wherein R3 is the radical xe2x80x94OR17 and R17 is a hydrogen atom.
This invention also features the salts of the compounds of formula (I) when R1 represents a carboxylic acid function, and the geometrical and optical isomers of said compounds of formula (I).
When the compounds according to the invention are in the form of salts, they are preferably salts of an alkali or alkaline earth metal, or, alternatively, of zinc or of an organic amine.
The FIGURE of Drawing sets forth reaction schemes/mechanisms illustrating representative syntheses for the preparation of the bicyclic aromatic compounds according to the present invention.
More particularly according to the present invention, by the term xe2x80x9clower alkyl radicalxe2x80x9d is intended an alkyl radical having from 1 to 12, preferably from 1 to 9, carbon atoms, advantageously the methyl, ethyl, propyl, isopropyl, butyl, tert-butyl, pentyl, hexyl, heptyl, nonyl, decyl and dodecyl radicals.
By the expression xe2x80x9clinear or branched alkyl radical having from 1 to 20 carbon atomsxe2x80x9d are particularly intended the methyl, ethyl, propyl, isopropyl, tert-butyl, octyl and 2-ethylhexyl radicals.
By the term xe2x80x9calkoxy radicalxe2x80x9d is intended an alkoxy radical preferably having from 1 to 9 carbon atoms, in particular the methoxy, propyloxy, pentyloxy and heptyloxy radicals.
By the term xe2x80x9cmonohydroxyalkylxe2x80x9d or xe2x80x9cpolyhydroxyalkylxe2x80x9d radical is intended a radical having from 1 to 6 carbon atoms and from 1 to 5 hydroxyl groups. Among such monohydroxyalkyl radicals, preferred are those having 2 or 3 carbon atoms, in particular a 2-hydroxyethyl, 2-hydroxypropyl or 3-hydroxypropyl radical. Among such polyhydroxyalkyl radicals, preferred are those having from 3 to 6 carbon atoms and from 2 to 5 hydroxyl groups, such as the 2,3-dihydroxypropyl, 2,3,4-trihydroxybutyl and 2,3,4,5-tetrahydroxypentyl radicals, or the pentaerythritol residue.
By the term xe2x80x9caryl radicalxe2x80x9d is preferably intended a phenyl radical optionally substituted with at least one halogen atom, lower alkyl radical, hydroxyl group, alkoxy radical, nitro function, polyether radical, or an amino function optionally protected with an acetyl group or optionally substituted with at least one lower alkyl radical.
By the term xe2x80x9caralkyl radicalxe2x80x9d is preferably intended a benzyl or phenethyl radical optionally substituted with at least one halogen atom, lower alkyl radical, hydroxyl group, alkoxy radical, nitro function, a polyether radical or an amino function optionally protected with an acetyl group or optionally substituted with at least one lower alkyl radical.
By the term xe2x80x9calkenyl radicalxe2x80x9d is preferably intended an alkenyl radical having from 2 to 5 carbon atoms and containing one or more sites of ethylenic unsaturation, such as, more particularly, the allyl radical.
By the term xe2x80x9cpolyether radicalxe2x80x9d is intended a radical having from 1 to 6 carbon atoms and from 1 to 3 oxygen or sulfur atoms, such as the methoxymethyl ether, methoxyethoxymethyl ether or methylthiomethyl ether radicals.
By xe2x80x9csugar residuesxe2x80x9d are preferably intended those derived, for example, from glucose, galactose, mannose or glucuronic acid.
By xe2x80x9camino acid residuexe2x80x9d is preferably intended one derived, for example, from at least one of the 20 amino acids of L or D configuration constituting mammalian proteins. More particularly intended are the residues derived from lysine, glycine or aspartic acid.
By xe2x80x9cheterocyclexe2x80x9d is preferably intended piperidino, morpholino, pyrrolidino or piperazino, optionally substituted in the 4-position with a C1-C6 alkyl radical or with a mono- or polyhydroxyalkyl radical as defined above.
Among the compounds of formula (I) according to the present invention, particularly representative are the following:
3-(3xe2x80x2,5xe2x80x2-Di-tert-butyl-2xe2x80x2-methoxy-3-biphenylyl)acrylic acid;
3-(2xe2x80x2-Benzyloxy-3xe2x80x2,5xe2x80x2-di-tert-butyl-6-hydroxy-3-biphenylyl)acrylic acid;
3-(3xe2x80x2,5xe2x80x2-Di-tert-butyl-6-hydroxy-2xe2x80x2-pentyloxy-3-biphenylyl)acrylic acid;
3-(3xe2x80x2,5xe2x80x2-Di-tert-butyl-6-hydroxy-2xe2x80x2-methoxy-3-biphenylyl)acrylic acid;
3-[3-(3-Benzyloxy-5,5,8,8-tetramethyl-5,6,7,8-tetrahydro-2-naphthyl)-4-methoxymethoxyphenyl]acrylic acid;
3-[3-(3-Benzyloxy-5,5,8,8-tetramethyl-5,6,7,8-tetrahydro-2-naphthyl)-4-hydroxyphenyl]acrylic acid;
[4-Methoxymethoxy-3-(3,5,5,8,8-pentamethyl-5,6,7,8-tetrahydro-2-naphthyl)phenyl]propynoic acid;
3-[3-(3-Propyloxy-5,5,8,8-tetramethyl-5,6,7,8-tetrahydro-2-naphthyl)-4-methoxymethoxyphenyl]acrylic acid;
3-[3-(3-Pentyloxy-5,5,8,8-tetramethyl-5,6,7,8-tetrahydro-2-naphthyl)-4-methoxymethoxyphenyl]acrylic acid;
3-(5xe2x80x2-Adamantan-1-yl-4xe2x80x2-methoxy-2xe2x80x2-methyl-3-biphenylyl)acrylic acid;
3-(5xe2x80x2-Adamantan-1-yl-6-hydroxy-4xe2x80x2-methoxy-2xe2x80x2-methyl-3-biphenylyl)acrylic acid;
3-(5xe2x80x2-Adamantan-1-yl-4xe2x80x2-methoxy-6-methoxymethoxy-2xe2x80x2-methyl-3-biphenylyl)acrylic acid;
3-{4-Methoxy-3-[3-(3-methoxybenzyloxy)-5,5,8,8-tetramethyl-5,6,7,8-tetrahydro-2-naphthyl]phenyl}acrylic acid;
3-{4-Methoxy-3-[3-(4-methoxybenzyloxy)-5,5,8,8-tetramethyl-5,6,7,8-tetrahydro-2-naphthyl]phenyl}acrylic acid;
3-{3-[3-(6-Hydroxyhexyloxy)-5,5,8,8-tetramethyl-5,6,7,8-tetrahydro-2-naphthyl]-4-methoxyphenyl}acrylic acid;
3-{3-[3-(7-Hydroxyheptyloxy)-5,5,8,8-tetramethyl-5,6,7,8-tetrahydro-2-naphthyl]-4-methoxyphenyl}acrylic acid;
3-{3-[3-(5-Hydroxypentyloxy)-5,5,8,8-tetramethyl-5,6,7,8-tetrahydro-2-naphthyl]-4-methoxyphenyl}acrylic acid;
3-{3-[3-(3-Hydroxypropyloxy)-5,5,8,8-tetramethyl-5,6,7,8-tetrahydro-2-naphthyl]-4-methoxyphenyl}acrylic acid;
3-[3-(1-Benzyloxy-5,5,8,8-tetramethyl-5,6,7,8-tetrahydro-2-naphthyl)phenyl]acrylic acid;
3-(3xe2x80x2-Adamantan-1-yl-4xe2x80x2-hydroxy-3-biphenylyl)acrylic acid;
5-[4-Methoxy-3-(5,5,8,8-tetramethyl-5,6,7,8-tetrahydro-2-naphthyl)phenyl]-3-methylpenta-2,4-dienoic acid;
5-[4-Methoxymethoxy-3-(5,5,8,8-tetramethyl-5,6,7,8-tetrahydro-2-naphthyl)phenyl]-3-methylpenta-2,4-dienoic acid;
5-[4-Hydroxy-3-(5,5,8,8-tetramethyl-5,6,7,8-tetrahydro-2-naphthyl)phenyl]-3-methylpenta-2,4-dienoic acid;
3-{3-[3-(5-Tert-butoxycarbonylpentyloxy)-5,5,8,8-tetramethyl-5,6,7,8-tetrahydro-2-naphthyl]-4-methoxyphenyl}acrylic acid;
3-{3-[3-(7-Tert-butoxycarbonylheptyloxy)-5,5,8,8-tetramethyl-5,6,7,8-tetrahydro-2-naphthyl]-4-methoxyphenyl}acrylic acid;
3-{3-[3-(7-Carboxyheptyloxy)-5,5,8,8-tetramethyl-5,6,7,8-tetrahydro-2-naphthyl]-4-methoxyphenyl}acrylic acid;
3-{3-[3-(5-Carboxypentyloxy)-5,5,8,8-tetramethyl-5,6,7,8-tetrahydro-2-naphthyl]-4-methoxyphenyl}acrylic acid;
3-{3-[3-(5-Carbamoylpentyloxy)-5,5,8,8-tetramethyl-5,6,7,8-tetrahydro-2-naphthyl]-4-methoxyphenyl}acrylic acid;
3-{3-[3-(7-Carbamoylheptyloxy)-5,5,8,8-tetramethyl-5,6,7,8-tetrahydro-2-naphthyl]-4-methoxyphenyl}acrylic acid;
3-{4-Methoxy-3-[5,5,8,8-tetramethyl-3-(2-morpholin-4-ylethoxy)-5,6,7,8-tetrahydro-2-naphthyl]phenyl}acrylic acid;
3-{4-Methoxy-3-[5,5,8,8-tetramethyl-3-(2-piperidin-1-ylethoxy)-5,6,7,8-tetrahydro-2-naphthyl]phenyl}acrylic acid;
3-{4-Methoxy-3-[3-(2-methoxymethoxybenzyloxy)-5,5,8,8-tetramethyl-5,6,7,8-tetrahydro-2-naphthyl]phenyl}acrylic acid;
3-{4-Methoxy-3-[3-(3-methoxymethoxybenzyloxy)-5,5,8,8-tetramethyl-5,6,7,8-tetrahydro-2-naphthyl]phenyl}acrylic acid;
3-{4-Methoxy-3-[3-(4-methoxymethoxybenzyloxy)-5,5,8,8-tetramethyl-5,6,7,8-tetrahydro-2-naphthyl]phenyl}acrylic acid;
3-{4-Methoxy-3-[3-(3-hydroxybenzyloxy)-5,5,8,8-tetramethyl-5,6,7,8-tetrahydro-2-naphthyl]phenyl}acrylic acid;
3-[4-Fluoro-3-(3,5,5,8,8-pentamethyl-5,6,7,8-tetrahydro-2-naphthyl)phenyl]acrylic acid;
3-{4-Hydroxy-3-[3-(3-methoxybenzyloxy)-5,5,8,8-tetramethyl-5,6,7,8-tetrahydro-2-naphthyl]phenyl}acrylic acid;
3-{4-Hydroxy-3-[3-(4-methoxybenzyloxy)-5,5,8,8-tetramethyl-5,6,7,8-tetrahydro-2-naphthyl]phenyl}acrylic acid;
3-{4-Hydroxy-3-[3-(4-fluorobenzyloxy)-5,5,8,8-tetramethyl-5,6,7,8-tetrahydro-2-naphthyl]phenyl}acrylic acid;
3-{4-Hydroxy-3-[3-(4-chlorobenzyloxy)-5,5,8,8-tetramethyl-5,6,7,8-tetrahydro-2-naphthyl]phenyl}acrylic acid;
3-[4-Hydroxy-3-(3-methoxymethoxy-5,5,8,8-tetramethyl-5,6,7,8-tetrahydro-2-naphthyl)phenyl]acrylic acid;
3-(3xe2x80x2,5xe2x80x2-Di-tert-butyl-6-hydroxy-2xe2x80x2-propyloxy-3-biphenylyl)acrylic acid;
3-(3xe2x80x2,5xe2x80x2-Di-tert-butyl-6-hydroxy-2xe2x80x2-butyloxy-3-biphenylyl)acrylic acid;
3-(2xe2x80x2-Butoxy-3xe2x80x2,5xe2x80x2-di-tert-butyl-6-methoxy-3-biphenylyl)acrylic acid;
3-(3xe2x80x25xe2x80x2-Di-tert-butyl-6-methoxy-2xe2x80x2-propoxy-3-biphenylyl)acrylic acid;
3-[4-Hydroxy-3-(5,5,8,8-tetramethyl-4-propoxy-5,6,7,8-tetrahydro-2-naphthyl)phenyl]acrylic acid;
3-[3-(3-Benzyloxy-5,5,8,8-tetramethyl-5,6,7,8-tetrahydro-2-naphthyl)-4-methoxyphenyl]acrylic acid;
Ethyl 3-[3-(3-benzyloxy-5,5,8,8-tetramethyl-5,6,7,8-tetrahydro-2-naphthyl)-4-methoxyphenyl]acrylate;
3-Methyl-5-[3-(3,5,5,8,8-pentamethyl-5,6,7,8-tetrahydro-2-naphthyl)phenyl]penta-2,4-dienoic acid;
3-[3-(3-Benzyloxy-5,5,8,8-tetramethyl-5,6,7,8-tetrahydro-2-naphthyl)-4-methoxyphenyl]prop-2-en-1-ol;
3-[3-(3-Benzyloxy-5,5,8,8-tetramethyl-5,6,7,8-tetrahydro-2-naphthyl)-4-methoxyphenyl]propenal;
N-Ethyl 3-[3-(3-benzyloxy-5,5,8,8-tetramethyl-5,6,7,8-tetrahydro-2-naphthyl)-4-methoxyphenyl]-acrylamide;
3-[3-(3-Benzyloxy-5,5,8,8-tetramethyl-5,6,7,8-tetrahydro-2-naphthyl)-4-methoxyphenyl]-1-morpholin-4-yl-propenone;
N-(4-Hydroxyphenyl)-3-[3-(3-benzyloxy-5,5,8,8-tetramethyl-5,6,7,8-tetrahydro-2-naphthyl)-4-methoxyphenyl]acrylamide;
5-(5xe2x80x2-Adamantan-1-yl-4xe2x80x2-methoxy-2xe2x80x2methyl-3-biphenylyl)-3-methylpenta-2,4-dienoic acid;
5-[4-Methoxymethoxy-3-(3,5,5,8,8-pentamethyl-5,6,7,8-tetrahydro-2-naphthyl)phenyl]-3-methylpenta-2,4-dienoic acid;
5-[4-Hydroxy-3-(3,5,5,8,8-pentamethyl-5,6,7,8-tetrahydro-2-naphthyl)phenyl]-3-methylpenta-2,4-dienoic acid;
4-[3-(3,5,5,8,8-Pentamethyl-5,6,7,8-tetrahydro-2-naphthyl)phenyl]penta-2,4-dienoic acid;
5-(3xe2x80x2,5xe2x80x2-Di-tert-butyl-2xe2x80x2-methoxy-3-biphenylyl)-3-methylpenta-2,4-dienoic acid;
5-(3xe2x80x2,5xe2x80x2-Di-tert-butyl-2xe2x80x2-propoxy-3-biphenylyl)-3-methylpenta-2,4-dienoic acid;
5-(2xe2x80x2-Butoxy-3xe2x80x2,5xe2x80x2-di-tert-butyl-3-biphenylyl)-3-methylpenta-2,4-dienoic acid;
5-(2xe2x80x2-Butoxy-3xe2x80x2,5xe2x80x2-di-tert-butyl-6-hydroxy-3-biphenylyl)-3-methylpenta-2,4-dienoic acid;
5-(3xe2x80x2,5xe2x80x2-Di-tert-butyl-6-hydroxy-2xe2x80x2-propoxy-3-biphenylyl)-3-methylpenta-2,4-dienoic acid;
5-(3xe2x80x2,5xe2x80x2-Di-tert-butyl-6-hydroxy-2xe2x80x2-methoxy-3-biphenylyl)-3-methylpenta-2,4-dienoic acid.
According to the present invention, the compounds of formula (I) which are more particularly preferred are those for which at least one, and preferably all, of the following conditions are satisfied:
R1 is a radical xe2x80x94COxe2x80x94R3;
Ar2 is a radical of formulae (d) or (e);
R11 is a radical xe2x80x94Oxe2x80x94R21;
R7 is a radical xe2x80x94Oxe2x80x94R20.
The present invention also features processes for preparing the compounds of formula (I), in particular according to the reaction scheme illustrated in the FIGURE of Drawing.
The compounds of formula (Ia) can be obtained (FIGURE of Drawing) from aldehyde or ketone derivatives (5), according to a Horner-type reaction with a lithium or sodium derivative of a phosphonate (7), it being possible for the carbonyl compounds (5) to be obtained either by a coupling reaction between a boronic acid (3) and a halo derivative (4) (this reaction is carried out in the presence of a palladium catalyst, for example tetrakis(triphenylphosphine)-palladium under the conditions described by N. Miyaura et al., Synthetic Communications, 11(7), 513-519 (1981); the boronic acid derivative (3) can be obtained, for example, from the halo derivative (1) by conversion into the lithium derivative (2) and then reaction with trimethyl borate and hydrolysis), or by a coupling reaction between a zinc derivative (8) and a halo ester derivative (9) in the presence of a catalyst, for example a palladium or nickel derivative (NiCl2dppe), followed by conversion of the ester function (10) into an alcohol (11) and oxidation into an aldehyde (5).
The compounds of formula (Ib) can be obtained from the acetylenic derivative (6) by reaction with n-butyllithium and then carboxylation in the presence of CO2.
The acetylenic compounds (6) can be obtained either:
from the aldehyde derivatives (5) (when R3 is a hydrogen atom), by reaction with carbon tetrabromide and triphenylphosphine to give a 2xe2x80x22xe2x80x2-dibromostyrene derivative which is converted into an acetylenic derivative by a non-nucleophilic base such as n-butyllithium in an aprotic solvent such as tetrahydrofuran, or
from the ketone derivatives (5) (when R3 is a lower alkyl radical) by a sequence of reactions comprising treatment with a base such as lithium diisopropylamide, then with a dialkyl phosphate chloride and again with lithium diisopropylamide.
When R1 is a xe2x80x94COOH radical, the compounds are prepared:
either by protecting R1 with a protecting group of alkyl, allylic or tert-butyl type.
Conversion to the free form can be carried out:
in the case of an alkyl protecting group, using sodium hydroxide or lithium hydroxide in an alcoholic solvent such as methanol or in THF;
in the case of an allylic protecting group, using a catalyst such as certain transition metal complexes in the presence of a secondary amine such as morpholine;
in the case of a protecting group of tert-butyl type, using trimethylsilane iodide.
When R1 is an alcohol function, the compounds can be obtained:
from the corresponding aldehyde derivatives by the action of an alkyl metal hydride, such as sodium borohydride, in an alcoholic solvent (for example methanol);
from the acid derivatives by reduction with lithium aluminum hydride.
When R1 is an aldehyde function, the compounds can be obtained from the alcohol derivatives by oxidation in the presence of manganese oxide, pyridinium dichromate or Swern""s reagent.
When R1 is an amide function, the compounds can be obtained from the corresponding carboxylic derivatives by reaction with aliphatic, aromatic or heterocyclic amines either via an acid chloride or in the presence of dicyclohexylcarbodiimide or carbonyldiimidazole.
Certain of the subject compounds bind to the RXR receptors, some having agonist activity, others having antagonist activity. The preferred compounds have antagonist activity.
The binding and transactivation properties as RXR-receptor agonists can be determined by methods known in the art, such as, for example: Levin et al., Nature, 355, 359-61 (1992); Allenby et al., Proc. Natl. Acad. Sci., 90, 30-4 (1993).
The RXR-agonist activity can also be determined by the test described in French patent application No. 95/07301, filed Jun. 19, 1995 by the assignee hereof. This test comprises the following steps: (i) a sufficient amount of a compound which is an active ligand for at least one receptor of the superfamily of steroidal/thyroid nuclear receptors other than a ligand specific for the RXR receptors and which can heterodimerize with the RXRs, such as an RAR-agonist molecule, is applied topically to an area of the skin of a mammal, (ii) a molecule capable of having RXR-agonist activity is administered systemically or topically to this same area of the skin of the mammal before, during or after step (i), and (iii) the response on the part of the mammal""s skin thus treated is evaluated. Thus, the response to topical application to a mammal""s ear of an RAR-agonist molecule which corresponds to an increase in the thickness of this ear can be increased by the systemic or topical administration of an RXR-receptor agonist molecule.
The RXRxcex1-antagonist activity can be evaluated in the transactivation test by determination of the dose (IC50) which gives 50% inhibition of the transactivating activity of an RXRxcex1-selective agonist: 6-[1-(3,5,5,8,8-pentamethyl-5,6,7,8-tetrahydro-2-naphthyl)cyclopropyl]nicotinic acid (CD 3127) according to the following procedure:
HeLa cells are co-transfected with an expression vector coding for RXRxcex1 (p565-RXRxcex1) and a reporter plasmid containing the response element xc2xd CRBP II cloned upstream of the thymidine kinase heterologous promoter and of the chloramphenicolm-acetyl-transferase (CAT) reporter gene. Eighteen hours after co-transfection, the cells are treated with a fixed concentration of CD 3127 and increasing concentrations of the molecule to be evaluated. After treatment for twenty-four hours, the CAT activity is assayed by ELISA. The fixed concentration of CD3127 used is 10xe2x88x928M and corresponds to its EC50.
The compounds according to the invention are particularly well suited in the following fields of therapy:
(1) for treating dermatological conditions associated with a keratinization disorder related to differentiation and on proliferation, in particular for treating common acne, comedones, polymorphonuclear leukocytes, rosacea, nodulocystic acne, acne conglobata, senile acne and secondary acnes such as solar, medication-related or occupational acne;
(2) for treating other types of keratinization disorders, in particular ichthyosis, ichthyosiform states, Darier""s disease, palmoplantar keratoderma, leucoplasias and leucoplasiform states, and cutaneous or mucous (buccal) lichen;
(3) for treating other dermatological conditions associated with a keratinization disorder manifesting an inflammatory and/or immunoallergic component and, in particular, all forms of psoriasis, whether cutaneous, mucous or ungual psoriasis and even psoriatic rheumatism, or, alternatively, cutaneous atopy, such as eczema or respiratory atopy, or gingival hypertrophy; the compounds can also be used for treating inflammatory conditions not exhibiting keratinization disorder;
(4) for treating all dermal or epidermal proliferations, whether benign or malignant and whether or not of viral origin or otherwise, such as common warts, flat warts and verruciform epidermodysplasia, oral or florid papillomatoses and the proliferations which can be induced by ultraviolet radiation, in particular in the case of basocellular and spinocellular epithelioma;
(5) for treating other dermatological disorders such as bullosis and collagen diseases;
(6) for treating certain ophthalmological disorders, in particular corneopathies;
(7) for repairing or combating aging of the skin, whether photoinduced or chronological, or for reducing actinic keratoses and pigmentations, or any pathologies associated with chronological or actinic aging;
(8) for preventing or curing the stigmata of epidermal and/or dermal atrophy induced by local or systemic corticosteroids, or any other form of cutaneous atrophy;
(9) for preventing or treating cicatrization disorders or for preventing or repairing stretch marks, or, alternatively, for promoting cicatrization;
(10) for combating disorders of sebaceous functioning, such as the hyperseborrhoea of acne or simple seborrhoea;
(11) for the treatment or prevention of cancerous or precancerous states;
(12) for the treatment of inflammatory conditions such as arthritis;
(13) for the treatment of any general or skin affliction of viral origin;
(14) for the prevention or treatment of alopecia;
(15) for the treatment of dermatological or general conditions including an immunological component;
(16) for the treatment of conditions of the cardiovascular system such as arteriosclerosis, hypertension, non-insulin-dependent diabetes and obesity;
(17) for the treatment of skin disorders due to an exposure to U.V. radiation.
In the therapeutic fields indicated above, the compounds according to the invention may advantageously be administered in combination with other compounds exhibiting retinoid-type activity, with D vitamins or derivatives thereof, with corticosteroids, with anti-free-radical agents, with xcex1-hydroxy or xcex1-keto acids or derivatives thereof, or, alternatively, with ion-channel blockers. By the expression xe2x80x9cD vitamins or derivatives thereofxe2x80x9d are intended, for example, vitamin D2 or D3 derivatives and in particular 1,25-dihydroxyvitamin D3. By xe2x80x9canti-free-radical agentsxe2x80x9d are intended, for example, xcex1-tocopherol, superoxide dismutase, ubiquinol or certain metal-chelating agents. By the expression xe2x80x9cxcex1-hydroxy or xcex1-keto acids or derivatives thereofxe2x80x9d are intended, for example, lactic, malic, citric, glycolic, mandelic, tartaric, glyceric or ascorbic acid or the salts, amides or esters thereof. Lastly, by the term xe2x80x9cion-channel blockersxe2x80x9d are intended, for example, Minoxidil (2,4-diamino-6-piperidinopyrimidine 3-oxide) and derivatives thereof.
The present invention thus also features medicinal compositions containing at least one compound of formula (I), one of the optical or geometrical isomers thereof, or one of the salts or other derivatives thereof.
The pharmaceutical/therapeutic compositions of this invention, intended especially for the treatment of the aforesaid disease states comprise a carrier, diluent or vehicle which is pharmaceutically acceptable and compatible with the mode of administration selected for the given composition, at least one compound of formula (I), one of the optical or geometrical isomers thereof, or one of the salts, etc., thereof.
The compounds according to the invention can be administered systemically, enterally, parenterally, topically or ocularly.
For enteral administration, the medicinal/pharmaceutical compositions may be in the form of tablets, gelatin capsules, sugar-coated tablets, syrups, suspensions, solutions, elixirs, powders, granules, emulsions, microspheres or nanospheres or polymeric or lipid vesicles which permit a controlled release. For parenteral administration, the compositions may be in the form of solutions or suspensions for perfusion or for injection.
The compounds according to the invention are generally administered at a daily dose of about 0.01 mg/kg to 100 mg/kg of body weight, and this at the regime or rate of 1 to 3 doses per diem.
For topical administration, the pharmaceutical compositions based on compounds according to the invention are more particularly intended for the treatment of the skin and the mucosae and may be in the form of ointments, creams, milks, salves, powders, pommades, impregnated pads, solutions, gels, sprays, lotions or suspensions. They may also be in the form of microspheres or nanospheres or polymeric or lipid vesicles or polymeric patches and hydrogels which permit controlled release. These topical-route compositions may either be in anhydrous form or in aqueous form, depending on the clinical indication.
For ocular administration, they are mainly eyedrops.
These compositions for topical or ocular application contain at least one compound of formula (I) as defined above, or one of the optical or geometrical isomers thereof, or one of the salts or other derivatives thereof, at a concentration preferably ranging from 0.001% to 5% by weight relative to the total weight of the composition.
The compounds of formula (I) according to the invention also find application in the cosmetic field, in particular for body and hair hygiene and especially for treating skin types with a tendency towards acne, for promoting the regrowth of the hair, for combating hair loss, for combating the greasy appearance of the skin or the hair, for protection against the harmful effects of the sun or for the treatment of physiologically dry skin types, and for preventing and/or combating photoinduced or chronological aging.
For cosmetic applications, the compounds according to the invention can moreover be employed advantageously in combination with other compounds of retinoid-type activity, with D vitamins or derivatives thereof, with corticosteroids, with anti-free-radical agents, with xcex1-hydroxy or xcex1-keto acids or derivatives thereof, or alternatively with ion-channel blockers, all of these various active agents being as defined above.
The present invention therefore also features cosmetic compositions comprising a cosmetically acceptable support (vehicle, diluent or carrier) which is suitable for topical application, at least one compound of formula (I) as defined above or one of the optical or geometrical isomers thereof, or one of the salts or other derivatives thereof. Such cosmetic compositions are advantageously in the form of a cream, a milk, a lotion, a gel, microspheres or nanospheres or polymeric or lipid vesicles, a soap or a shampoo.
The concentration of the compounds of formula (I) in the cosmetic compositions according to the invention advantageously ranged from 0.001% to 3% by weight relative to the total weight of the composition.
The medicinal and cosmetic compositions of the present invention can also contain inert additives and adjuvants, or even pharmacodynamically or cosmetically active additives and adjuvants, or combinations of these additives and adjuvants, in particular: wetting agents; depigmenting agents such as hydroquinone, azelaic acid, caffeic acid or kojic acid; emollients; moisturizing agents such as glycerol, PEG 400, thiamorpholinone and derivatives thereof, or urea; anti-seborrhoea or anti-acne agents such as S-carboxymethylcysteine, S-benzylcysteamine, the salts and the derivatives thereof, or benzoyl peroxide; antibiotics such as erythromycin and esters thereof, neomycin, clindamycin and esters thereof, and tetracyclines; antifungal agents such as ketoconazole or 4,5-polymethylene-3-isothiazolinones; agents for promoting the regrowth of the hair, such as Minoxidil (2,4-diamino-6-piperidinopyrimidine 3-oxide) and derivatives thereof, Diazoxide (7-chloro-3-methyl-1,2,4-benzothiadiazine 1,1-dioxide) and Phenytoin (5,5-diphenylimidazolidine-2,4-dione); non-steroidal anti-inflammatory agents; carotenoids and, in particular, xcex2-carotene; anti-psoriatic agents such as anthraline and derivatives thereof and, lastly, eicosa-5,8,11,14-tetraynoic acid and eicosa-5,8,11-triynoic acid, the esters and the amides thereof.
The compositions according to the invention may also contain flavor-enhancing agents, preservatives such as para-hydroxybenzoic acid esters, stabilizing agents, moisture regulators, pH regulators, osmotic pressure modifiers, emulsifying agents, UV-A and UV-B screening agents, and antioxidants such as xcex1-tocopherol, butylhydroxyanisole or butylhydroxytoluene.